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The efficacy of peroxisome proliferator-activated receptor α-agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH. Pemafibrate efficacy was assessed in a diet-induced rodent model of NASH compared with fenofibrate. Pemafibrate and fenofibrate improved obesity, dyslipidaemia, liver dysfunction, and the pathological condition of NASH. Pemafibrate improved insulin resistance and increased energy expenditure significantly. To investigate the effects of pemafibrate, we analysed the gene expressions and protein levels involved in lipid metabolism. We also analysed uncoupling protein 3 (UCP3) expression. Pemafibrate stimulated lipid turnover and upregulated UCP3 expression in the liver. Levels of acyl-CoA oxidase 1 and UCP3 protein were increased by pemafibrate significantly. Pemafibrate can improve the pathogenesis of NASH by modulation of lipid turnover and energy metabolism in the liver. Pemafibrate is a promising therapeutic agent for NAFLD/NASH.

Background: The C/C genotype of a polymorphism in the uncoupling protein3 (UCP3) promoter (-55C->T) (rs1800849) is associated with an increased body mass index. Objective: The aim of our study was to investigate the effect of polymorphism on the UCP3 promoter (-55C->T) on insulin resistance and cardiovascular risk factors secondary to a high protein/low carbohydrate vs. a standard hypocaloric diets (1,000 kcal/day). Design: A population of 283 obese subjects was analyzed in a randomized trial. A nutritional evaluation was performed at the beginning and at the end of a 9-month period in which subjects received 1 of 2 diets (diet HP: high protein/low carbohydrate vs. diet S: standard diet). Results: Weight improvement was higher in non-T carriers. With both diets and only in wild genotype (diet HP vs. diet S), total cholesterol (-9.7 ± 4.0 vs. -11.1 ± 2.0 mg/dl; p > 0.05) and low density lipoprotein (LDL) cholesterol (-8.3 ± 3.0 vs. -5.5 ± 2.7 mg/dl; p > 0.05) decreased. The improvement in these parameters was similar in subjects with diet HP than HS. With diet HP and only in wild genotype, glucose (-5.2 ± 2.2 mg/dl; p < 0.05), triglycerides (-15.5 ± 3.9 mg/dl; p < 0.05), insulin levels (-3.9 ± 3.1 UI/l; p < 0.05) and homeostasis model assessment (HOMA-R; -0.6 ± 0.1 units; p < 0.05) decreased. Conclusion: Carriers of T allele have a different response than non-carrier subjects, with a lack of decrease of LDL cholesterol, glucose, insulin levels and HOMA-R. The weight loss was lower in T carriers. HP diet showed a better metabolic response than S diet in 55CC homozygous.

Background The impact of vitamin D3 (VD3) on obesity has been reported in the past. Our study was aimed at investigating the possible mechanisms by which VD3 affects obesity induced by a high fat diet. Methods Eight-week-old C57BL/6 J male mice were fed a normal- or high-fat diet for 9 weeks and were treated with a gavage of vehicle (corn oil) or cholecalciferol (50 μg/kg, daily). Body weight, white adipose tissue weight, blood lipid and glucose levels were measured. In addition, we investigated the expression of 1,25(OH) 2 D 3 (calcitriol)/VDR-regulated genes involved in energy and lipid metabolism, such as of uncoupling protein 3 (UCP3), by using qRT-PCR in the liver, adipose tissue, skeletal muscle and C2C12, L6, and H-EMC-SS cells. We also measured UCP3 promoter transcription in the same cell lines using a Dual Luciferase Assay. Furthermore, we analyzed the binding site consensus sequences of VDR on the UCP3 promoter. Results Mice consuming a high-fat diet treated with cholecalciferol had lower body weight and adipose tissue weight and higher expression of UCP3 compared to the other treatment groups. Changes in the expression of genes correlated with calcitriol/VDR. Luciferase activity was dose-dependently associated with calcitriol/VDR levels. We confirmed the functional VDR binding site consensus sequences at -2200, -1561, -634, and +314 bp in the UCP3 promoter region. Conclusion We suggest that VD3/VDR inhibits weight gain by activating UCP3 in the muscles.

Background/Aims: Excessive salt intake and left ventricular hypertrophy (LVH) are both critical for the development of hypertension and heart failure. The uncoupling protein 3 (UCP3) plays a cardio-protective role in early heart failure development. However, the potential role for UCP3 in salt intake and LVH is unclear. Methods: UCP3 -/- and C57BL/6 mice were placed on either a normal-salt (NS, 0.5%) or a high-salt (HS, 8%) diet for 24 weeks. The cardiac function, endurance capacity, energy expenditure, and mitochondrial functional capacity were measured in each group. Results: Elevated blood pressure was only observed in HS-fed UCP3 -/- mice. High salt induced cardiac hypertrophy and dysfunction were observed in both C57BL/6 and UCP3 -/- mice. However, the cardiac lesions were more profound in HS-fed UCP3 -/- mice. Furthermore, HS-fed UCP3 -/- mice experienced more severe mitochondrial respiratory dysfunction compared with HS-fed C57BL/6 mice, represented by the decreased volume of oxygen consumption and heat production at the whole-body level. Conclusion: UCP3 protein was involved in the incidence of high-salt induced hypertension and the progression of cardiac dysfunction in the early stages of heart failure. UCP3 ablation exacerbated high-salt-induced cardiac hypertrophy and cardiac dysfunction.

An early insulin regimen ameliorates glucotoxicity but also lipotoxicity in type 2 diabetes; however, the underlying mechanism remains elusive. In the present study, we investigated the role of mitochondria in lipid regulation following early insulin administration in insulin-resistant skeletal muscle cells. Male C57BL/6 mice, fed a high-fat diet (HFD) for 8 weeks, were treated with insulin for 3 weeks, and L6 myotubes cultured with palmitate (PA) for 24 h were incubated with insulin for another 12 h. The results showed that insulin facilitated systemic glucose disposal and attenuated muscular triglyceride accumulation in vivo. Recovery of AMP-activated protein kinase (AMPK) phosphorylation, inhibition of sterol-regulated element binding protein-1c (SREBP-1c) and increased carnitine palmitoyltransferase-1B (CPT1B) expression were observed after insulin administration. Moreover, increased ATP concentration and cellular energy charge elicited by over-nutrition were suppressed by insulin. Despite maintaining respiratory complex activities, insulin restored muscular uncoupling protein 3 (UCP3) protein expression in vitro and in vivo. By contrast, knockdown of UCP3 abrogated insulin-induced restoration of AMPK phosphorylation in vitro. Importantly, the PA-induced decrease in UCP3 was blocked by the proteasome inhibitor MG132, and insulin reduced UCP3 ubiquitination, thereby prohibiting its degradation. Our findings, focusing on energy balance, provide a mechanistic understanding of the promising effect of early insulin initiation on lipotoxicity. Insulin, by recovering UCP3 activity, alleviated energy surfeit and potentiated AMPK-mediated lipid homeostasis in skeletal muscle cells following exposure to PA and in gastrocnemius of mice fed HFD.

Uncoupling proteins (UCPs) are members of the mitochondrial anion carrier superfamily involved in the control of body temperature and energy balance regulation. They are currently proposed as therapeutic targets for treating obesity and metabolic syndrome (MetS). We studied the gene expression regulation of UCP1, -2, and -3 in abdominal white adipose tissue (WAT) from control and MetS rats treated with two doses of a commercial mixture of resveratrol (RSV) and quercetin (QRC). We found that UCP2 was the predominantly expressed isoform, UCP3 was present at very low levels, and UCP1 was undetectable. The treatment with RSV + QRC did not modify UCP3 levels; however, it significantly increased UCP2 mRNA in control and MetS rats in association with an increase in oleic and linoleic fatty acids. WAT from MetS rats showed a significantly increased expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ when compared to the control group. Furthermore, PPAR-α protein levels were increased by the highest dose of RSV + QRC in the control and MetS groups. PPAR-γ expression was only increased in the control group. We conclude that the RSV + QRC treatment leads to overexpression of UCP2, which is associated with an increase in MUFA and PUFA, which might increase PPAR-α expression.

Uncoupling protein 3 (UCP3) is mainly expressed in muscle. It plays an important role in muscle, but less research on the regulation of cattle UCP3 has been performed. In order to elucidate whether cattle UCP3 can be regulated by muscle-related factors, deletion of cattle UCP3 promoter was amplified and cloned into pGL3-basic, pGL3-promoter and PEGFP-N3 vector, respectively, then transfected into C2C12 myoblasts cells and UCP3 promoter activity was measured using the dual-Luciferase reporter assay system. The results showed that there is some negative-regulatory element from −620 to −433 bp, and there is some positive-regulatory element between −433 and −385 bp. The fragment (1.08 kb) of UCP3 promoter was cotransfected with muscle-related transcription factor myogenic regulatory factors (MRFs) and myocyte-specific enhancer factor 2A (MEF2A). We found that UCP3 promoter could be upregulated by Myf5, Myf6 and MyoD and downregulated by MyoG and MEF2A.

The growing interest in how exercise and carbohydrate (CHO) restriction may modify molecular responses that promote endurance adaptations has led to many interesting controversies. We conducted a systematic review and a meta-analysis regarding the effect of low-carbohydrate availability (LOW) pre-, during, or post-exercise, on the mRNA content of commonly measured genes involved in mitochondrial biogenesis (PGC-1α, TFAM mRNA) and metabolism (PDK4, UCP3 and GLUT4 mRNA), and on muscle glycogen levels, compared with a high-CHO (CON) condition. MEDLINE, Scopus, and Web of Science databases were searched following the PRISMA 2020 guidelines (with an end date of November 2023). In total, 19 randomized-controlled studies were considered for inclusion. We evaluated the methodological quality of all studies using the Cochrane Risk of Bias tool for randomized clinical studies. A meta-analysis was performed using a random effects model to calculate the standardized mean difference (SMD), estimated by Hedges' g, and 95% confidence intervals (CIs). The LOW condition was associated with an increased mRNA content of several genes during the early recovery period post-exercise, such as PDK4 (SMD 1.61; 95% CI 0.80-2.42), GLUT4 (SMD 1.38; 95% CI 0.46-2.30), and UCP3 (SMD 2.05; 95% CI 0.40-3.69). However, overall, there was no significant effect on the mRNA content of PGC-1α or TFAM. Finally, CHO restriction and exercise significantly reduced muscle glycogen levels (SMD 3.69; 95% CI 2.82-5.09). A meta-analysis of subgroups from studies with a difference in muscle glycogen concentration of > 200 mmol kg dw between the LOW and CON conditions showed an increase in exercise-induced PGC-1α mRNA (SMD 2.08; 95% CI 0.64-3.52; p = 0.005; I  = 75%) and a greater effect in PDK4 and GLUT4 mRNA. The meta-analysis results show that CHO restriction was associated with an increase in the exercise-induced mRNA content of PDK4, UCP3, and GLUT4, but not the exercise-induced mRNA content of PGC-1ɑ and TFAM. However, when there were substantial differences in glycogen depletion between CON and LOW CHO conditions (> 200 mmol kg dw ), there was a greater effect of CHO restriction on the exercise-induced mRNA content of metabolic genes, and an increase in exercise-induced PGC-1α mRNA.

Heat stress has been reported to reduce uncoupling proteins (UCP) expression, which in turn should improve mitochondrial efficiency. Such an improvement in efficiency may translate to the systemic level as greater exercise economy. However, neither the heat‐induced improvement in mitochondrial efficiency (due to decrease in UCP), nor its potential to improve economy has been studied. Determine: (i) if heat stress in vitro lowers UCP3 thereby improving mitochondrial efficiency in C2C12 myocytes; (ii) whether heat acclimation (HA) in vivo improves exercise economy in trained individuals; and (iii) the potential improved economy during exercise at altitude. In vitro, myocytes were heat stressed for 24 h (40°C), followed by measurements of UCP3, mitochondrial uncoupling, and efficiency. In vivo, eight trained males completed: (i) pre‐HA testing; (ii) 10 days of HA (40°C, 20% RH); and (iii) post‐HA testing. Pre‐ and posttesting consisted of maximal exercise test and submaximal exercise at two intensities to assess exercise economy at 1600 m (Albuquerque, NM) and 4350 m. Heat‐stressed myocytes displayed significantly reduced UCP3 mRNA expression and, mitochondrial uncoupling (77.1 ± 1.2%, P < 0.0001) and improved mitochondrial efficiency (62.9 ± 4.1%, P < 0.0001) compared to control. In humans, at both 1600 m and 4350 m, following HA, submaximal exercise economy did not change at low and moderate exercise intensities. Our findings indicate that while heat‐induced reduction in UCP3 improves mitochondrial efficiency in vitro, this is not translated to in vivo improvement of exercise economy at 1600 m or 4350 m. Heat stress down‐regulates UCP3 mRNA expression thereby improving mitochondrial efficiency in C2C12 myocytes. However, the enhanced mitochondrial efficiency does not translate to improved submaximal exercise economy in humans, following heat acclimation.

Branched-chain amino acids (BCAAs), including leucine (Leu), isoleucine (Ile), and valine (Val), are key regulators of protein synthesis in muscle. The aim of this study was to investigate the effect of different BCAA ratios (Leu:Ile:Val) on the proliferation, differentiation, and expression levels of the regulators related to protein metabolism of C2 C12 myocytes. Studies were conducted in C2C12 myocytes exposed to different BCAA ratios (Leu: Ile: Val = 0, 1:0.25:0.25, 1:1:1). The ratio of 1:0.25:0.25 increased cell viability and promoted cell cycle progression from G0/G1 phase to S phase, which was an indicator of proliferation enhancement (P < 0.05). Moreover, this optimal ratio (1:0.25:0.25) promoted the differentiation of myocytes into myotubes by upregulating myogenin and interleukin-15 gene expression, and differently regulated the expression of L-type amino acid transporter 1 and 4 and system ASC amino acid transporters 2. Furthermore, the ratio stimulated mTOR expression at the mRNA and phosphorylated protein levels, as well as ribosomal protein S6 kinase and regulatory-associated protein of mTOR (raptor). In contrast, the optimal ratio decreased the amount of ubiquitin ligase muscle-specific RING finger 1 and muscle atrophy F-box during proliferation and differentiation (P < 0.05). No change was observed in the expression of key genes related to energy metabolism except for uncoupling protein 3 (P > 0.05). The results suggested that appropriate BCAA ratios could enhance proliferation and differentiation of the C2 C12 myocytes, also mediate the key regulators related to protein metabolism including the mTORC1 pathway. A proper utilization of balanced BCAA ratio in food would be beneficial to human and animal nutrition. •Optimal branched-chain amino acid (BCAA) ratio promoted myocytes proliferation and differentiation.•Optimal BCAA ratio activated the nutrient sensor mTORC1 pathway of myocytes.•The expression level of myogenic factors of myocytes was regulated by different BCAA ratios.